The Immune System and Pregnancy

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To most people, "tolerating a baby" means getting through sleepless nights, endless infections and colds, teething and tantrums. But in reality a baby has to be "tolerated" long before the demands of parenthood. In fact the process begins from the moment of conception because a developing baby is genetically distinct from the mother, and that means persuading the immune system not to attack what is effectively foreign tissue.

For instance, if you received a transplanted kidney or liver, you would be given drugs to suppress your normal immune response and advised to protect yourself from potential infections, since your normal defensive systems are reduced. Even so, there would still be a risk that you might reject the donated organ.

But a mother-to-be receives no such treatment when she is pregnant. Instead she has to programme her immune system to tolerate the presence of foreign genes donated by the father. If she rejects them, she will reject the developing child.

Sadly, this is the cause of some spontaneous miscarriages, and it's also thought to be the cause of pre-eclampsia, a syndrome that affects 2-5% of women across the globe.

It usually presents in the last three months of pregnancy and causes high blood pressure and proteinuria (protein in the urine). It is also associated with inadequate development and attachment of the baby's placenta to the wall of the uterus, and poor maternal placental blood flow.

Both of these factors can compromise the rate of growth of the baby, which can be picked up by routine assessments during pregnancy and on scans, but the other signs may be harder to spot, at least initially, because they are often asymptomatic. This can make the condition harder to diagnose, although one giveaway is that the syndrome usually resolves promptly as soon as the baby is delivered, and in severe cases this may be the only option to protect mother and child, even if it means the baby is born several weeks early. This is because, left untreated, pre-eclampsia can be fatal.

But, surprisingly, the cause of the condition is still not known. Many theories have been put forward over the years, but no single one of them explains all of the symptoms. Pre-eclampsia has features of both an immunological and a genetic condition. For example, mother A may have pre-eclampsia with father B during her first pregnancy, but her subsequent pregnancies proceed normally. But if mother A changes partner to father C, then the original risk of pre-eclampsia returns. This demonstrates that after an initial pregnancy with father B the mother's immune system somehow becomes tolerant to father B's genes. This implies some component of memory within the mother's immune system.

The problem is certainly partner-specific; a woman can experience pre-eclampsia with one partner but not another, which re-enforces the idea that the father's genetic background is important.

Immune rejection of the foetus is thought to be caused by an incompatibility between the genetic backgrounds of the mother and baby at the place where the two meet, known as the maternal-foetal interface.

This interface offers a unique site where both mother and child coexist for 9 months, but without any immune challenge in the vast majority of pregnancies. This has intrigued many evolutionists and caused debate as to how the process of live birth originally arose. Did evolution of tolerance towards the foetus drive a co-evolution of the immune system?

In recent years research has focused on a group of white blood cells, called natural killer or NK cells, that may also play a role in the process. They form part of what is known as the "innate immune system", meaning that they have the ability to recognise and in some cases destroy foreign material, without having been exposed to it previously. Normally NK cells are found in lymph nodes, blood and other immune-specific sites, and their chief role is to seek out and destroy infected and cancerous cells, and to act as the first-line defence in the body.

But scientists have recently uncovered a specialised sub-set of these cells, known as uterine NK (uNK) cells, which seem to play a key role in controlling the environment of the maternal-foetal interface, although their origin and precise roles are still unknown.

These cells were first documented in 1902 by a scientist called Jenkinson, but at the time, due to their shape and location, they were thought to be glandular tissue concerned with nourishing the lining of the uterus; consequently they were referred to as Granulated Metrial Gland Cells (GMG cells). It wasn't until 1991 that scientists proved that these GMG cells were white blood cells with all the features of NK cells.

Since then, scientists have found that uNK cells play a key role in policing and controlling the environment of the maternal-foetal interface. In particular they promote the growth of new blood vessels (angiogenesis) and the dilatation of the blood vessels which supply the placenta. This helps to ensure that the developing foetus receives sufficient energy and raw materials required for growth, and that waste products are efficiently removed. uNK cells also control the growth of the foetal trophoblast, which is the tissue that invades the wall of the uterus to anchor the developing foetus to its mother, and produce the placenta. But despite their common origins, it's also clear that uNK cells are also not the typical (NK) killers found in the rest of the body.

As part of my research in the Laboratory of Lymphocyte Signalling and Development at Babraham Institute, I am studying these cells to try to understand how paternal genes affect the chances of developing pre-eclampsia. Some of the key questions we're grappling with include where uNK cells come from? Do they follow the same developmental pathway as their NK relatives found in the rest of the body? And do paternal genes affect uNK cells? If so, where, when and how is this interaction taking place? So, for the moment at lesat, these cells are a Pandora's box of pregnancy!

What we do know is that there are some key genes which have the potential to increase the risk of pre-eclampsia when they occur in combination with certain other paternal genes. Hopefully, as we learn more about the actions of these genes, we will be able to screen sperm prior to fertility treatment. This would enable doctors to avoid using sperm that carry gene combinations that might increase the risk of pre-eclampsia, which should help to increase the success rate.

But work in humans has obvious problems. Primarily, the ethical issues involved in performing experiments on the tissue of aborted or miscarried foetuses make it difficult for scientists to obtain such tissue. Another problem is that scientists cannot control for the different genetic makeup of each of the parents. In an ideal world we would be able to genotype humans and then encourage them to mate, but this isn't realistic and nor is the nine-month wait for the results!

Instead, mice can be used to "model" the condition and they offer a number of advantages over human subjects. Not only is the genetic makeup of mice well defined and relatively easy to manipulate, but mice also have a short gestation period, and strategic mating can be used to track down the genetic triggers of pre-eclampsia.

The implications and potential of this research area drive my passion for this subject, which combines pregnancy, organ rejection, immunology and evolution. There are few topics that allow such a narrow focus on one cell type, but that have such huge implications for the whole of biology, including the human species.

I'll leave you with one consideration and one question: Firstly, I hope that next time you look at a weary new mother, you will appreciate what her immune system has already been through! Secondly, if a mother's immune system has to change and use specialised cells to deal with a foetus that contains half of its genes from the father, how do surrogate pregnancies work?